Role of elevated S-adenosylhomocysteine in rat hepatocyte apoptosis: Protection by betaine

Abstract

Previous studies from our laboratory have shown that ethanol consumption results in an increase in hepatocellular S-adenosylhomocysteine levels. Because S-adenosylhomocysteine is a potent inhibitor of methylation reactions, we propose that increased intracellular S-adenosylhomocysteine levels could be a major contributor to ethanol-induced pathologies. To test this hypothesis, hepatocytes isolated from rat livers were grown on collagen-coated plates in Williams' medium E containing 5% FCS and exposed to varying concentrations of adenosine in order to increase intracellular S-adenosylhomocysteine levels. We observed increases in caspase-3 activity following exposure to adenosine. This increase in caspase activity correlated with increases in intracellular S-adenosylhomocysteine levels and DNA hypoploidy. The adenosine-induced changes could be significantly attenuated by betaine administration. The mechanism of betaine action appeared to be via the methylation reaction catalyzed by betaine-homocysteine-methyltransferase. To conclude, our results indicate that the elevation of S-adenosylhomocysteine levels in the liver by ethanol is a major factor in altering methylation reactions and in increasing apoptosis in the liver. We conclude that ethanol-induced alteration in methionine metabolic pathways may play a crucial role in the pathologies associated with alcoholic liver injury and that betaine administration may have beneficial therapeutic effects. Published by Elsevier Inc.

Inhibition of adiponectin production by homocysteine: A potential mechanism for alcoholic liver disease

“…Recent studies from several groups, including ours, documented that chronic alcohol consumption not only caused a decrease in hepatic SAM levels, but also an elevation in SAH levels, leading to a markedly decreased SAM/SAH ratio, an indicator of abnormal transmethylation status. [13][14][15] Furthermore, we showed that accumulation of SAH in the liver sensitized to tumor necrosis factor ␣ (TNF-␣)-induced hepatotoxicity. 14 It is now well accepted that adipose tissue is a much more active tissue than originally thought and that it plays a critical role in the regulation of energy homeostasis and inflammatory reactions in other tissues, including liver and skeletal muscle.…”

“…These alterations are thought to be involved in the pathogenesis of ALD. [10][11][12][13][14][15] Ji and Kaplowitz 12 reported increased hepatic homocysteine accumulation in an intragastric alcohol infusion animal model of ALD and postulated that hyperhomocysteinemia-induced endoplasmic reticulum stress might be implicated in hepatocyte death in alcohol-fed mice. Recent studies from several groups, including ours, documented that chronic alcohol consumption not only caused a decrease in hepatic SAM levels, but also an elevation in SAH levels, leading to a markedly decreased SAM/SAH ratio, an indicator of abnormal transmethylation status.…”

Betaine improved adipose tissue function in mice fed a high-fat diet: a mechanism for hepatoprotective effect of betaine in nonalcoholic fatty liver disease

“…It is also a metabolite of choline and an essential biochemical component of the methionine-homocysteine cycle (8). Hepatoprotective effects of betaine were reported in a variety of experimental animal models of liver diseases, including alcoholic liver disease and bile acid-induced liver injury (4,11,15,18), with different mechanisms involved. The therapeutic effects of betaine on NAFLD have also been investigated and reported in both clinical and experimental studies (1,17,21,24,28).…”

Effects of dechlorane plus on the hepatic proteome of juvenile Chinese sturgeon (Acipenser sinensis)

“…In addition, betaine homocysteine methyltransferase (BHMT) is an enzyme responsible for remethylation of homocysteines to form methionine. Suppression of this enzyme can result in increased generation of homocysteine and an increased activity of antioxidant enzymes (Kharbanda et al, 2005;Moat et al, 2000). In a previous study, De Wit et al (2008) found that BHMT was down-regulated in the liver of zebrafish after TBBPA exposure, and concluded that this was a result of oxidative stress.…”